Project Summary The unifying theme this proposal is polyether synthesis via epoxide-opening cascades. The methods constitute a new strategy for the synthesis of polyethers of the ladder structural class (similar to brevetoxin and other Red Tide toxins) and emulate the epoxide cascade biogenesis proposed by Nakanishi and Nicolaou. The utility of these efficient epoxide-opening cascades is demonstrated in the syntheses of ladder polyether natural products and derivatives of biomedical relevance. The methods are developed with generality in mind and the syntheses are designed for flexibility. Thus, an important component of this proposal is the preparation of specific compounds suitable for testing. The diseases targeted include cystic fibrosis (brevenal and structural variants), and the necessary collaborations for these activities have already been established. The development of new methods of synthesis and the study of the reaction mechanisms involved in these processes are critical for the achievement of these goals and thus are under intense investigation.